Process for the synthesis of 1-alkyl-8-methyl hexahydroindanone-4



Patented Sept. 17, 1946 2,407,672

UNITED STATES PATENT, OFFICE PROCESS FOR THE SYNTHESIS OF l-ALKYL- S-METHYL HEXAHYDROINDANONE-4 I Nicholas A. Milas, Belmont, Mass, assignor to Research Corporation, New York, N. Y., a corporation of New York e No Drawing. Application June 20, 1941, Serial No. 399,040

10 Claims. (Cl. 260468) 1 2 V In the synthesis of the antirachitic vitamins, Compound III is then alkylated to give Comthe ketone Compound I constitutes an important pound IV by heating it for several hours with 6- intermediate product. The present invention et y1- -b 0 odo pt i t e P e deals with a new process for the synthesis of this of Sodium potasslum alloy DOtaSsium. tal ketone using a solvent such as toluene or xylene;

CH8 I CH: .011, R H am /CH1 HawH] H l/ 10 IC[CH2]a-CH 2 r o o H H: CH: /7\ /1\ CH3 0 l H206 80 2011, Compound III+ --d I I I Na-K or K sand H20 O-C 0 0 02H;

9 3 (toluene or xylene) I I HflC5\4/C\'CHI heat H2O 0:0

(1?, H 7 Compound IV 0 d1 compo When Compound IV is refluxed with sodium ethylate, the cyclopentanone ring opens and sub-i sequently closes again but in a different fashion Although R preferably is the hydrocarbon sideto produce Compound V. chain .found in the natural antirachitic vitamins, it is not restricted thereto but may be hydrogen or any other monovalent aliphatic hydrocarbon .25 E radical. i i H 'CI1"[CH11i-CH The present process makes use of the well 0-H CH: known diethyl adipate, Compound II, or any oompmmdw 29? other suitable ester of adipic acid. Through the 30 heat H 0.00 H well known process of cyclization with metallic sodium or sodium ethylate in a suitable solvent, H Compound 11 is converted to z-carboethoxy cy- CompoundV clopentanone-l, Compound III.

That Compound V is actually produced may be (300mm shown by the positive ferric chlorid reaction on, H; which is not given by Compound IV because the (13H! Naoczm latter contains no active enolyzable hydrogen mo c-coocim 40 atom. j 7 (3:0 Compound V can also be prepared by hydro- CH2 k lyzing Compo'undIV with hot dilute sodium eth- CIwOCZHB m ylate orbarium hydroxide to give the open chain dicarboxylic. acid Compound VI which upon es- H terification and subsequent cyclization in the 3 presence of sodium or sodium ethylate is easily converted to Compound V.

0003 CH: amalgamated zinc to give Compound XII.

H g H-C-C-[CH2]a-C 5 (UV NaOCzHKdil.) CH3 CH3 00002115 Ompoun or BMOH)a H2 Compound XI Br-CH (Aq') 5 CHE-CHPCOOCHH} OH: 0 Zn OH followed by hydrolysis Compound VI (7H5 /CH3 The diethyl ester of Compound VI has also [O zlaOH been prepared by an alternative route through H QH CH3 the reaction of a-bIOIllOELdiPiC ester, Compound 0000 VII, and methyl isohexylketone, Compound VIII, z in the presence of zinc dust or wool and subse- H quently reducing catalytically the Compound IX. H

COOCzHt 20 00002115 0 rCH H a Zn dust C (CH3)2C-[OH2] =0 CHg-CHg-CHn-COOCnH; 00002115 or wool Z d--t- 1 I1 I15 01 W00 Compound VIII (in benzene 'or toluene heat) Compound XII Compound VII 7 00062115 This product, Compound MI, is easily dehydrated by heating with small amounts of iodine COOCBHE CH3 or p-toluene sulfonic acid to give Compound XIII. CH3 /.CH3 .H g[GH]a-0 C=C'[CH]3'CH Ni or Pt"+ H, H cm H, 0 \CH8 I Compound XII I CH3-CH2C 0 0 03H; 01 p-toluene CHz-CHg-Z O'CHg d th 1 t f sulfonic acid 16 85 BI 0 Compound IX 0 y VI (3H3 /CHa tic-{onion When Compound V is treated with magnesium H in ethyl alcohol .or with sodium ethylate, the v mag'nesio or sodio salt, Compound X, is formed 40 0 00002115 which reacts with ethyl chloroformate to give C=C CH2CH2 COO 0,115 Compound XI. Mg C O 0 02115 Compound V 'or, NaO CaHa H20 (IJHB (3H3 00002115 E(|l-[CH]3CH(CH;): HC-(CHDaCE XIII H/-C H-C CH; 1 m0 Compound XIII is then hydrolyzed with alco- ClCOOCzHs 0 00 C holic potash, and the tetracarboxylic acid, Com- 2 5 pound XIV, formed is decarboxylated by heating with copper powder under reduced pressure to (Na) form Compound XV, in which the double bond 2 has rearranged to conjugate with on of the car- Compound XI CompoundX boxyl groups.

(I311: H(|3-[CHz]aCH(CH3)z H-C alcoholic heat Compound XIII -0 H2O C=CCH1CH1COOH potash Cu powder 7 COOH H20-CCOOH coon Compound XIV (111: CH; fla w ah H 1]a a):

1| Esterify l 11-0 --v C acid catalyst H3O C--C1I2CH:CH3C00H H3O CCH2CHn--CHz-C'OOC:H5

Compound XI is then treated with oc-bIOlilO or chloro glutaric diethyl ester in the presence of l H2OCC O 0 0 H,

Compound XVI Compound XV can easily be esterified with absolute alcohol in the presence of an acid catalyst and'the resulting Compound XVI cyclized according to the method of Dieckmann using metallic sodium or sodium ethylate in an inert atmosphere whereby Compounds XVII and XVIII successively are formed. Compound XVIII upon treatment with methyl magnesium iodide gives Compound I, the desired product, by a 1,4-addition.

Na Compound XVI toluene or xylene H-C CH, hydrolysis 320 o cm 07,

.. \C/fi Compound XVII CH3 CH CHr%[OH2]aCH(CHa): H-[CHzIrCfi H-C CH: CH3 CH CH3 20 fil (IJHr Mg H7C\ /Cg| H: C OH: I H20 0 CH:

C HaC-C B: t r I PG CompoundXVIII CompoundI Compound XVI, one of the key intermediates, can also be synthesized by the following alternative route. This proceeds through the preparation of the halogeno Compound XIX from Compound IV. Compound XIX is then easily converted to the phenoxy Compound XX by treatment with" sodium phenolate.

Compound XIX Compound XIX sodium phenolatlez NaBr When Compound XX is hydrolyzed with alkali and the salt formed isacidified with dilute hydrochloric acid, the acid Compound XXI is so i formed, which latter, upon heatingwith copper powder, goes over easilyto CompoundXXII When Compound XXII is treated with o-methoxy n-butyl magnesium bromide in anhydrous ether and the product is hydrolyzed in the usual manner, Compound XXIII is formed, which latter can easily be converted to Compound XXIV by heating withsmall quantities of iodine or ptoluene sulfonic acid, or by treatin with thionyl chloride in the presence of a tertiary base. Compound XXIV can be easily hydrogenated catalytically to Compound XXV.

ether followed by hydrolysis Compound XXII Compound XXV When Compound XXV is hydrolyzed With either hydriodic or hydrobromic acid Compound IQIVI is formed, which latter can be converted to Compound XXVII by oxidation with chromic acid. The sodium salt of Compound XXVII is then treated with sodium cyanide and the nitrile n me is d ol e b bo l n wi h, I h rochloric acid yielding Compound XXVIII. This is esterifiedand the resulting diester dehydrated to form, Compound I.

CrOa

in (1. 11:80; or acetic acid Compound XXVII No.0 N

esa Compound XXVII v followed by acidification esterification C 2115 O H acid catalyst COOH Compound xxvm --v by heat with I:

diester of Compound XXXIII Compound XIUX is then hydrolized with alcoholic potash, and the hydrolyzed product is partly decarboxylated by heating with copper powder to form Compound XXX.

I I by acidi- H2C.CO CsHs fication H and heat 7 a 7 Compound XXX 7 Compound XXX is catalytically hydrogenated and the product hydrolyzed:- with hydrobromic acid to form compound XXXI,

Compound XXXI is then oxidized with chromic acid to Compound XXVII, followed by reaction with NaC N to form the nitrile compound, and the latter is hydrolyzed to Compound XXVJII from which Compound XVI can be prepared as Compound XVI can also he prepared by react- A more detailed account of the principal and novel reactions of the present process is to be found in the following:

Z-carboethoxy cyclo-pentanone-l (94 g.) was dropped slowly into 22.9 g. of potassium sand in 635 g. of anhydrous xylene heated in an oil bath to 125-130: To this mixture was then added 150 g. of 6-methyl-2-iodo heptane and the mixture heated at 130 135 for 43 hours. After cooling to room temperature, water was added to the mixture and the xylene layer separated; the latter was washed three times with water, dried, and fractionated under reduced pressure, the product boiling at 165-170 (14 mm.) being collected; yield, 55 g.; B. P. at 3 mm. 142-146; no 1.4473. This ketone does not give a color with ferric chloride.

The ketone was also prepared in about 18% yields by using sodium-potassium alloy and the corresponding 6-methyl-2 bromo heptane and z-carboethoxy cyclopentanone l and refluxing the mixture for 70 hours at 135-140.

Synthesis of 5- [1 ,5-dimethyl] -hexyl-2-carboethomy cyclopentanone 1-Compound V 4 Twenty-six g. of 2-[1',5'-dimethyl]-hexyl carboethoxy cyclopentanone-l .was dissolved in the minimum quantity of absolute ethyl alcohol and to this was added'3 g. of metallic sodium. The mixtur was then refluxed for eight hours, cooled, poured into water and neutralized with diluted hydrochloric acid. The aqueous mixture was extracted several times with ether, the ethereal extract was dried and thereafter was fractionated under reduced pressure, the product boiling between 190-205 (20 mm.) being collected and used for the nextstep. The fact of such a wide melting point range is probably due to the presence of cis and trans isomers in the mixture. This product gives the ferric chloride coloration while Compound IV does not, showing that it has undergone the rearrangement shown above.

Hydrolysis of Compound IV and preparation of Compound VI Compound V may also be prepared from Compound 1v yia the Compound v1 by hydrolyzing Compound IV in hotdilute alcoholic solution of sodium ethylate or by boiling for everal hours with aqueous barium hydroxide. In both cases the salt of the acid Compound VI is formed. Compound VI can be obtained by acidifying with dilute hydrochloric acid and extracting with ether. By esterification and cyclization, Compound V may be formed. The diethyl ester of Compound IV can easily be prepared by heating Compound IV with absolute ethyl alcohol in-the presence of small quantities of sulfuric acid.

The diethyl ester of Compound VI may also be prepared by reacting, in dry benzene, oc-bIOmO- adipic ester VII withmethyl isohexyl ketone VIII in thepresence of amalgamated zinc dust or wool,

using small amounts of iodine to catalyze the reaction. 'Product IX is isolated from'the reaction and is easily converted to the diethyl ester product VI by catalytic hydrogenation in alcohol using platinum oxide or nickel catalyst.

Cyclization of the diethyhester of Compound VI to form Compound V The ketone CompoundV is prepared by cyclization of the diethyl ester Compound VI using the well known Dieckmann method by heating in toluene with metallic sodium. The principal product formed is ketone Compound V, which latter is separated by fractional distillation under reduced pressure.

Synthesis of 2,2 dicarboethoaty 5 [ll',5'-dimethyl] -he:cyl cyclopentanone 1Compound XI f An equivalent quantity of Compound V is treated in anhydrous other with one mole of ethylmagnesium bromide, and to the product, Come pound X, without separating it from the solvent, is added one mole of ethyl chloroformate; the mixture, is well stirred for several hours. At the end of the reaction the product is treated with water, the ethereal solution is separated, and from the latter Compound XI is isolated and purified.

synthesis of 1-carboetho:vy-2-carboethorybutyl- 5- [1',5-dimethyl] -he:ryl cyclopentene-A1,2 Compound XVI Compound XVI is prepared by a series of simple reactions as follows:

Compound XI is heated in anhydrous toluene with an equivalent quantity of a-bromoglutaric diethyl ester in the presence of amalgamated zinc for several hours. The reaction is activated from time to time by the addition of small quantities of iodine. At the end of the reaction the product is poured in water and the toluene layer separated and dried. This gives Compound XII. When a few crystals of iodine or anhydrous p-toluene sulfonic acid is added and the mixture heated, water splits out and distils over yielding Compound XIII. Finally, the tolu ne is removed and the product saponified by heating on the water bath with 10% alcoholic potash. The mixture is then poured in water, acidified with hydrochloric acid and the organic acid extracted with ether. When Synthesis of ketone Compound I from Compound XVI One mole of metallic sodium is treated in anhydrous toluene under reflux with vigorous stirthen cooled and poured in water and the toluene ring to produce finely divided sodium. To the mixture is then added slowly one mole of Compound XVI. After all of Compound XVI has been added, the mixture is heated for several. hours,

layer separated, dried and the toluene removed.

The toluene-free residue is purified by fractionation under reduced pressure. The product, Compound XVII, is then saponified by heating on thewater bath with alcoholic potash, poured into water, and the mixture is acidified with hydrochloric acid and extracted with ether. When the ether is removed from the extract the product,

upon heating, loses carbon dioxide very easily to i r 12 5. in the process of producing a compoundof the formula IcIaim:

1. a new product, a compound of the formula lz on-3 GHO pound of'the formula H C'OOnilkyl ZIH 0 000.81k'y1 J/ c'o Oialkyl wherein Z represents a substituent of the group consisting of hydrogen and a. mohovalent a-liphatic hydrocarbon radical, s'aponi'fying and decmomcmo o O.alky1 carboxyl'ating the latter, and esterifying the de- 4 carboxylated product to yield a compound of wherein Z is a substituent of the group conw hei'i b e iis asubstiwe'nt ofjth'e group sisting of hydrogen and a monovalent aliphatic 5 consisting O y i1 and a "inofi'ovale'nt alihydrocarbon radical. phatic hydrocarbon radical.

"6. I In the processor producing a "compound of the formula 4. Process which comprises cyclizing a co pound of the formula wherein Z represents a substituent of the group consisting of hydrogen and a monovalent ali-, phatic hydrocarbon radical, and thereafter replacing the metallo radical by a .carboxyalkyl radical to produce a compound of the formula cooamyrwherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical, reacting the latter product with an alpha halogeno glutaric dialkyl ester in the presence of zinc, hydrolyzing and dehydrating the resulting product to yield a compound of the formula Z H C O O.alkyl CHz.CH2.CH2-C O O.alkyl the formula wherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical, the steps Which comprise halogenating a compound of the formula Z O O .alkyl H-C l 2C=O 4 a H- -H 1i i wherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical, to introduce a halogen substituent in the 3-position, reacting the halogenated compound with sodium phenolate whereby to substitute a phenoxy radical for the halogen substituent in the 3-position, hydrolyzing with alkali and then acidifying with dilute mineral acid whereby to convert the -COO.alkyl group in the l-position to COOH, and heating the resulting carboxylic acid compound with cop- 14 per powdersto produce a compound of the for-n mula I 3 E Z H H-( J 2C=O H-( l-o 00115 0 wherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical,v treating the latter with t-methoxy-n-butyl magnesium bromide in anhydrous medium and then hydrolyzing, whereby to form a compound of the formula l :I O.CaH5 wherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical, successively dehydrating, hydrogenating and hydrolyzing the latter, oxidizing the resulting 3-hydroxy compound with chromic acid to form a 3-keto compound, converting the 3-keto compound to the corresponding nitrile, and hydrolyzing with mineral.

acid to yield a compound of the formula wherein Z represents a substituent of the group consisting of hydrogen and ,a monovalent aliphatic hydrocarbon radical, and successively esterifying and dehydrating the resulting product whereby to produce a compound of the formula 151 C0O.alky1 wherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical.

8. Process of producing a compound of the formula wherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical, which comprises hydrolyzing a compound of the formula wherein Z represents a substituent of the group 15 consisting of hydrogen and a monovalent ali-' phatic hydrocarbon radical, partially decarboxylating the hydrolyzed product to produce a compound of the formula wherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical, hydrogenating the latter and thereafter hydrolyzing the hydrogenated product, oxidizing the hydrolyzed compound .to the corresponding B-keto compound, converting the 3-keto compound to the corresponding nitrile, and hydrolyzing the latterto the corresponding dicarboxylic acid, esterifying the acid and dehydrating the resulting diester.

9. Process of producing a compound of .the formula wherein Z represents :a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical, to yield a compound of the :formula ill wherein Z represents a substituent of the group consisting of hydrogen and a monovalent aliphatic hydrocarbon radical, esterifying the latter open chain dicarboxylic acidcompound, and cyclizing the esterifiedcompound. V

10. Process of producing a compound of the formula yield a compound of the formula 0 o 0 .alkyl catalytically hydrogenating the latter compound,

and cyclizing the hydrogenated product.

- NICHOLAS A. MILAS. 

